The Subclinical Vascular Contributions to Alzheimer’s Disease: The Multi-Ethnic Study of Atherosclerosis (MESA) Multisite Study of AD

Improving vascular health is identified as a potential strategy to delay the onset of Alzheimer’s disease (AD); however, few vascular targets are implicated because the potential mechanisms remain unclear. Arterial stiffness is emerging as such a key vascular factor for late life dementia, through associations with various aspects of AD-related pathology including: cerebral small vessel disease, β-amyloid deposition and brain atrophy in AD-prone regions. However, gaps in this mechanism resulting in mechanical damage in brain remain. Partly because no existing studies have has adequate data to: a) examine the independent temporal associations of these age-dependent phenomena, b) determine at-risk individuals or groups, and c) directly connect arterial stiffness to aspects of AD pathology through its effects on cerebral blood flow. We propose to address these gaps in our knowledge by leveraging >15 years of highly detailed longitudinal vascular data from Multi-Ethnic Study of Atherosclerosis (MESA). The ‘MESA Multisite AD study’ will add: a) repeated, detailed cognitive assessments (over 2.5 years) to adjudicate cognition and assess cognitive changes over time; b) repeated MRI (over 2.5 years) to assess neurodegeneration, cerebrovascular disease and cerebral perfusion; d) Aβ-PET imaging to quantify Aβ burden; and e) a brain donation program. The ‘MESA Multisite AD study’ will contribute key findings and unique resources relating antecedent subclinical vascular disorders to AD pathology and cognitive decline. Specifically, it will address the role of changes arterial stiffness and hemodynamic pathways to AD-related pathology. This approach will be an efficient and cost-effective open-resource for researchers to identify antecedent modifiable vascular and metabolic risk factors (over >15 years) for AD and will help guide the development of novel therapeutic targets or prevention strategies for various forms of AD-related dementias.